High doses of cisplatinum have shown substantial activity in metastatic melanoma. Interferon-alfa is another active agent in this disease and has been shown to potentiate the cytotoxicity of platinum in vitro. Interleukin-2 (IL-2) in combination with interferon-alfa has synergistic antitumor activity in animal models and appears to mediate responses through activation of the host immune system. Since animal models have demonstrated synergistic anti-tumor activity when agents with direct cytotoxic effects are combined with immunomodulators, we combined interferon-alfa/platinum with interferon-alfa/IL-2 in an attempt to improve the therapeutic outcome in metastatic melanoma patients. Interferon-alfa 5 mu/m2 was administered subcutaneously on days 0-3, 7-10, 15-18 and 22-25. Cisplatinum (100 mg/m2 in the first 4 patients, 75 mg/m2 in the next 5 patients) was infused over 30 minutes in hypertonic saline on days 1 and 8. IL-2 was given on days 15-18 and 22-25 by continuous infusion at a dose of 3 mu/m2/d (total 96 hours of infusion for each week). A bolus of IL-2 (3 mu/2) was given prior to the infusion on day 15 and 22, and additional boluses (1.5 mu/m2) were given on days 16-18 and 23-25. Three of 9 evaluable patients responded in adrenal, skin, lung, and lymph node sites. One additional patient had a 50% reduction in tumor measurements (skin and soft tissue) followed by surgical resection of residual disease. Responses were transient (2.5-7 months) except for one patient who continues in a partial remission at 14+ months. Toxicity was excessive and included intolerable nausea and vomiting, fatigue, creatinine elevation, myelosuppression, confusion, pruritus, and transaminase elevation. Although the regimen was active, there was no indication that a high rate of complete responses could be achieved, and toxicity was too severe to justify continued patient accrual. The study has been closed.